Brain Phospholipid Metabolism, In Relation To Function

体内代谢(1)被剥夺3代营养必需n-3 （omega-3）多不饱和脂肪酸（PUFAs）的大鼠出现学习记忆缺陷。脑磷脂显示n-3二十二碳六烯酸浓度降低，n-6花生四烯酸浓度无变化，n-6二十二碳五烯酸浓度升高。脑磷脂中二十二碳六烯酸的周转率明显降低，但仍具有活性，而花生四烯酸的周转率不变。脑功能和结构取决于二十二碳六烯酸和花生四烯酸之间的竞争。周转率似乎是由特定的酶组独立调节的。(2)在大鼠中，每天3-5%的脑花生四烯酸和2-8%的脑二十二碳六烯酸分别由血浆中未酯化的pufa替代。在人类中，花生四烯酸的替代率是每天0.3%。根据测量的脑内PUFA浓度，大鼠的半衰期为1-2周，人的血浆脑内PUFA替代半衰期为10周。疾病状态下PUFA的补充可以通过膳食补充来增强。(3)放射性标记花生四烯酸可用于心脏和大脑的磷脂代谢成像和定量。当在未麻醉的大鼠体内静脉注射时，它被选择性地结合到心脏的膜磷脂中。(1)临床方案开始使用PET成像花生四烯酸和二十二碳六烯酸进入人脑。慢性酒精中毒、双相情感障碍和帕金森病可以用这种方法进行研究。(2)我们的脂肪酸方法提示帕金森病患者脑多巴胺能信号过度活跃，导致运动异常。在帕金森病大鼠模型（黑质慢性单侧病变）中，对多巴胺能D2受体激动剂的反应，基底神经节-额叶皮质回路静脉注射放射性花生四烯酸的摄取增加。该受体偶联磷脂酶A2的激活和花生四烯酸的释放进行信号转导。(3)大鼠长期服用多巴胺能D2拮抗剂氟哌啶醇，可减少血浆中放射性标记的花生四烯酮在基底神经节-额叶皮层回路中的掺入。氟哌啶醇的抗精神病作用可能是由于这些回路中d2受体介导的花生四烯酸信号的下调。(4)在DS脑中升高的肌醇在Ts65Dn小鼠DS模型中也升高。因此，该模型可用于研究肌醇升高对信号传导和磷脂酰肌醇循环的影响。

In vivo metabolism (1) Rats deprived of nutritionally essential n-3 (omega-3) polyunsaturated fatty acids (PUFAs) for 3 generations had deficits in learning and memory. Their brain phospholipids showed a reduced concentration of n-3 docosahexaenoic acid, no change in the concentration of n-6 arachidonic acid, and an increased concentration of n-6 docosapentaenoic acid. The turnover rate of docosahexaenoate in brain phospholipids was markedly reduced but nevertheless active, whereas the turnover rate of arachidonic acid was unchanged. Brain function and structure depend on competition between docosahexaenoic and arachidonic acids. The turnover rates appear to be independently regulated by specific sets of enzymes. (2) In rats, 3-5% of brain arachidonic acid and 2-8% of brain docosahexaenoic acid are replaced daily by the respective unesterified PUFAs from plasma. In humans, the arachidonate replacement rate is 0.3% per day. Based on measured brain PUFA concentrations, these rates give half-lives of 1-2 weeks in rats and 10 weeks in humans for brain PUFA replacement from plasma. PUFA replacement in disease states can be enhanced by dietary supplementation. (3) Radiolabeled arachidonic acid can be used to image and quantify phospholipid metabolism in heart as well as in brain. When injected intravenously in unanesthetized rats, it is selectively incorporated into membrane phospholipids in the heart. In vivo Imaging (1) Clinical protocols were initiated to use PET to image incorporation of arachidonic and docosahexaenoic acids into the human brain. Chronic alcoholism, bipolar disorder and Parkinson disease can be studied with this method. (2) Our fatty acid method suggests that brain dopaminergic signaling is hyperactive in Parkinson disease, accounting for abnormal motor movements. In a rat model of Parkinson disease (chronic unilateral lesion of substantia nigra), uptake of intravenously injected radioactive arachidonic acid into basal ganglia-frontal cortex circuitry was increased ipsilateral to the lesion, in response to a dopaminergic D2 receptor agonist. This receptor is coupled to phospholipase A2 activation and the release of arachidonic acid for signal transduction. (3) Chronic administration to rats of the dopaminergic D2 antagonist, haloperidol, decreased radiolabeled arachidonic incorporation from plasma into basal ganglia-frontal cortex circuits. Haloperidol's antipsychotic effect may be due to downregulation of D2-receptor mediated arachidonate signaling in these circuits. (4) Myoinositol, which is elevated in the DS brain, also is elevated in the brain of the Ts65Dn mouse model for DS. This model thus can be used to study the effect of myoinositol elevation on signaling and the phosphatidylinositol cycle.